Cephalosporins and Aminoglycosides

8/3/2019 Cephalosporins and Aminoglycosides

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CH2S

CHCHNHCR1

Cephalosporins

CNC=OO7ACP

R2

C

C = O

(effectsmetabolismandpharmacokinetic)

R1 decides:antibacterial activityresistance to -lactamase

OH

stability for stomach acids

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7ACP: 7-aminocephalosporanic acid

Acylation of PBPs

Inhibition of PBPs

Cephalosporins

M G M G M G

M G M G M G

MInhibits cross linking

of peptidoglycan

Cell lysis

Structural irregularities

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Classification : Best indicated by generationbased on antimicrobial activity

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Cefazolin (ANCEF,ZOLICEF, others)Cefadroxyl (DURACEF)Cefalexin monohydrate(KEFTAB)

Ist generation

good against Gram (+);modest against Gram (-)Streptococci (except penncillin- resistant strains);

Useful spectrum

Cefradine (VELOSEF) Staphylococcus aureus (except Methicillin-resistant strain)

Cefuroxime (ZINACEF)Cefuroxime axetil

IInd generation Increased activity againstGram (-) but much lessactive than IIIrd generation

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Cefprozil (CEFZIL)Cefmatazole (ZEFAZONE)Loracarbef (LORABID)

Gram (-) e.g., Enterobacter sp, Klebsiella sp.,haemophilus influenza; Not active against gram + as Ist generation



Cefotaxime (CLAFORAN)

Ceftriaxone (ROCEPHIN)Cefdinir (OMNICEF)Cefditoren ivoxil SPECTRACEF

IIIrd generation

Less active than Istgeneration against Gram(+) but more active

Useful spectrum

Ceftizoxime (CEFIZOX)Ceftibuten (CEDAX)Cefpodoxime proxetil (VANTIN)Cefoperazone (CEFOBID)Ceftazidime (FORTAZ, others)

including

-lactamase producing bacteria

Active agnst Pseudomonas

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IV generation

Cefepime (MAXIPINE)

activity than IIIrd generation

and have increased stability against hydrolysis by -lactamase

Ceftobiprole (Zeftera / Zevtera )

5th generation

active against MRSA (methicillin-resistant Staphylococcalaureus, penicillin-resistant Streptococcus pneumoniae,

It has been shown to be statistically non ‐inferior to the combination of vancomycin and ceftazidime for the treatment of skin and soft tissue infections.

Ceftobiprole inhibits the PBP. Ceftobiprole is resistant to ‐ .



Mechanism of Resistance:Same as penicillin's. i.e. Altered PBPs or lactamase

First generation cefazolin is more susceptible to -lactamase from S aureaus than is Cephalothin

Third generation: susceptible to hydrolysis by induciblechromosomally encoded (Class 1 -lactamase)

Fourth generation: less susceptible

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General features of the Cephalosporins

•absorbed readily after oral administration

Distribution

•Several cephalosporins can penetrate intoCSF meningitis

•Can also cross placenta

•High concentrations also seen in synovial, bile andericardial fluids

•Penetration in aqueous humor of eye is high

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Excretion

Primarily excreted by kidneydosage should be adjusted in patients withrena nsu c ency

Cefoperazone (excreted in bile)

cefotaxime is deacelated in vivo; the metaboliteless active

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Specific Agents:

Ist generation:

Cefazolin

Well-tolerated after either IM or IVConc in plasma after 1g IM administration reach to 64 ug/ml

Excreted by glomerular filtration and is bound to plasmaproteins (85%)

frequently due to longer half-life

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II nd generation:

Cefoxitin

Resistant to -lactamse produced by Gram (-) rodsFor Gram (+) < active than I st generation cephalosporinsMore active than I st or IInd generation agents agnst -fragalis

Conc in plasma after 1g IM administration reach to 22 ug/ml;half life 40 min

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Cefotetan

More active than Cefoxitin agnst Gram (-)

Conc in plasma after 1-g IM administration reach to 70 ug/ml;half life 3.3 hrs

IIIrd generation:

Cefotaxime

-agnst most Gram (+) and (-) bacteria except B . fragilis

Half life in plasma 1 hrMetabolized desacetylcefotaxime

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Active agnst Gram (+) excellent for Pseudomonas andOther Gram (-) bacteria

III rd generation:

Ceftazidime

IV th generation:

Cefepime

.

ct ve agnst many entero act w c are res stant toother Cephalo

Excellent penetration in CSF;Conc in plasma after 2-g IV administration reach to126-193 ug/ml; half life 2 hrs 55

Therapeutic Uses:First generation : skin and soft tissue infections, surgical

prophylaxis of wound infection.

Third generation:infections caused by Klebsiella, Enterobacter, Proteus etc ,ceftriaxone : all forms of gonorrhea, severe lyme diseasescefotaxime or ceftriaxone : used to treat meningitis due topneumococci, meningococci, and Haemophillus influenza

Fourth generation noscomal infections whereresistance to -lactum antibiotics is expected.

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Hypersensitivity: The frequency of cross-reactivity withpenicillin-sensitive individuals is 5 to 15%.CONTRAINDICATED in patients with a history of anaphylaxis

Untoward Reaction:

to a penicillin.

Nephrotoxic

Renal tubular necrosis i.e. cephaloridine (4g/day)

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Hyperprothrombinemia,, Platelet dysfunction

ThrombocytopeniaDisulfiram-like Effect : cefamandole, cefotetan,moxalactam, cefoperazone.

Drug-drug Interactions:

Concurrent administration of Cephalosporins or gentamicincause nephrotoxicity (in >60 yr old patients)

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OTHER -LACTAM Antibiotics

Carbapenems (fused -lactum ring and a 5-membered ring sys)

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Imipenem :i. Mechanism of action: Binds to PBPs, disrupting cell wall

synthesis and is bactericidal.

ii. Spectrum: Broad-spectrum covers Gram (+) & Gram (-)e.g. Streptococci, Enterococci.

Resistant to most forms of -lactamase , includingthat produced by staphylococcus.

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iii. Metabolism:

not absorbed orally

Rapidly hydrolyzed by dipeptidase , so alwaysadministered with cilastatin , an inhibitor of dipeptidase

half life 1hr

70% recovered in urine as the active drug; renalinsufficiency

iv. Side effects:

patients allergic to the penicillins may demonstratecross-reactivity with imipenem.

nausea and vomiting.

Seizures have been reported with high doses.61

iv. Therapeutic Use:urinary tract and lower respiratory infections

--

effective against cephallosporin resistant bacteria

prudent to use imipenem for empirical treatmentof serious infections in hospitalized patients who haverecvd other -lactums

should NOT be used as monotherapy againstpseudomonas due to risk of resistance during therapy

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Meropenem (MERREM IV):

does not require cilastatintoxicity~imipenem

Therapeutics equivalent to Imipenem but less likelyto cause seizures

Ertapenem (INVANZ):

thus once daily dose

Gram (+) bacteria

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Aztreonam (AZACTAM)

A monocyclic -lactam ( a monobactam ).

i. Mechanism of action: Interacts with PBPs and induces theformation of long filamentous bacteria

ii. Spectrum: It more closely resembles the spectrum of theaminoglycosides. No activity against Gram (+) andanaerobic bacteria are resistant .

Aztreonam is resistant to the -lactamase producedby Gram (-) organisms.

iii. Side effects: well tolerated. Penicillin allergic patients donot exhibit cross-reactions with aztreonam .

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-Lactamase Inhibitors:

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Mechanism of action:

i. Inhibits -lactamase prevent the destruction of -lactun sensitive antibodies.

-.(the enzymes that degrade ceftazidine/cefotaxime).

However, inactive against -lactamaseproduced by treatment with IInd and IIIrdgeneration cephalosopirns.

iii. Poor antimicrobial activity, but binds irreversibly with -

ac amase rom o gram + or gram - ac soknown as “SUICIDE " inhibitor of -lactamase

iii. well absorbed; included in combination withamoxacillin (Augmentum) or with ticaricillin (TIMENTIN)

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Vancomycin

Complex tricyclic glycopeptide antibiotic

Mechanism : Inhibits cell wall polymerization by binding toterminal D-Ala-D-Ala terminus of incoming complexattached to carrier

P-P-C55MG MG

P-P-C55

MG( )n

+

MG( )n

67Vancomycin

Antibacterial activity:

Gram( –) are resistant because D-ala-D-ala (target) issubstituted with D-ala-D-ser or D-ala-D-lactate

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Absorption, Distribution and excretion:

Oral absorption poor; slow IV is preferred, NEVER IM(dose should be adjusted to maintainmdesirable troughlevels)

appears in body fluids and CSF

90% excreted by glomerular filtration;accumulates if renal function is im aired

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(can be cleared by hemodialysis)

Untoward Effects:Hypersensitive Reacns (macular skin rashes, anaphylaxis,Chills)

Rapid administration flushing, tachycardia,hypotension, erythematous or urticarial reacn

flushing “red-neck” or “red-man” syndrome bydirectly inducing toxicity in mast cells

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caution with the use of aminoglycosides



Summary

Inhibits enzymes inducing cell wallVancomycinbacitracin *Penn/cephaCarbapenemsAztreonam

-lactamse inhibitorsAffects bact. growth bybinding PBP’s and/or -lactamase

Resistance is developedPBPs, efflux pumps, cell wall, location of -lacatamase

Common Side effect: Hypersensitivity

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Drugs inhibiting Protein Synthesis

Aminoglycosides and Macrolides

Teteracycline and Chloramphenicol



Protein Synthesizing machinery

Ribosomebacteria has 50S and 30 S subunit which forms 70 S

ol some that slides on mRNA

mRNA

has A, P and E sites for binding with tRNA

forms template for protein synthesis

tRNA

attaches to 30s ribosomes

brings amino acids

attaches to A, P and E sites of ribosomes

Overview:



PA

E

Transferase

E



E PA



Eukaryotes : 60S and 40 S subunit

Why antibiotic drugs do not inhibit mammalian proteinsynthesis??

Difference in ribosomal units is the basis of selectivity of antimicrobial drugs against bacteria

Aminoglycosides

Gentamicin composed of amino-sugars

AmikacinNetilmicinKanamycinStreptomycin

water-soluble (hydrophillic)highly polarized



Kanamycin

2-deoxystreptamine

Kanamycin A,BTobramycinamikacin

streptidine

Streptomycin

Bacterial killing concentration dependent

Post-antibiotic effect persists after the serum conc <minimum inhibitory concentration (MIC)

Once daily dose of aminoglycosides is therefore efficacious



AGAminoglycosides Entry

a. Diffusion through porins

Periplasmicspace

PG

PBP PBP

rate limiting requiresnegative inner membranepotential

electron-transport chain

b. Energy-Dependent Phase 1(EDP1)

c) Create fissure inducing bacterial damage (contrastfrom Tetra or Chloram) further enhancing AG uptake(EDP2 phase)



Entry/effectiveness

pHCa 2+ /Mg2+

HyperosmolarityAnearobic conditions

(Abcess,hyperosmolaracidic urine)

Mechanism of Action:

a) binds to A site of 30s of ribosome subunit

i. interfere with the formation of the initiation complex

ii. induce misreading of the mRNA template

. remature term nat on o m trans at oniv. cause polysomes to break up into monosomes



Mechanisms of Resistance

Intracellular penetration

Low affinity of

drug for bacterialribosomes

ribosomal binding

siteGrouptransferases

acetylation, phosphorylation,aden lation of OH or NH2 r rug nact vat on

Metabolites can also compete with AG

Cross-resistance by other aminoglycosidesi.e. gentamicin tobramicin, amikamicin, kanamycin and

netilmycin.



AAC: acetylases; ANT: adenylase; APH, phosphorylase



Poor oral or rectal administrationRapidly absorbed from IM

VI. Absorption

20

30q24h

q8hthreshold

Single dose preferred

hours4 8 12 16 20 240

0

10

asma concentrat ons a ter n ect on o . mg gto a hypothetical patient either as a single (q24h) oras three divided doses (q8h)



Distribution

Do not cross BBB and do not achieve highdistribution in body fluids.

Excreted entirely via the kidneys.

Clearance faster from plasma as compared to

Excretion

tissues

Clearance similar in adults and children older than 6months; half life is prolonged in infants

e osage must e a uste or rena unct on.Should not be administered to patients in renalfailure



V. Spectrum:

Aerobic Gram (-) bacilli.Kanamycin and Streptomycin: limited spectrum

.

ou no e use or n ec ons causeby Serratia or P.aeruginosa

Ist -line drug for pseudomonas.

May be given with penicillin in infectionscaused b stre tococci Listeria s .

Anaerobic or facultative anaerobic bacteriaare resistant

IX. Side Effects

Ototoxicity

(vestibular and auditory dysfunction)

Largely irreversible



1

3

Cochlea, normally lined with hair cells that are destroyed by high concentrations of aminoglycosides. Aminoglycosides damage hair cells, especially in turn No. 1 and part of turn No. 2. Hairs are shed by the damaged cells to give loss of high-frequency response first(associated with turn No. 1) and low-frequency loss later (associated with turn to. 3).

1

23

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amikacin, kanamycin, neomycin

loss of high frequency tones

streptomycin and gentamicin

vestibular damage

loss of low frequency tones

oop ure cs urosem e an e acryn cacid) potentiate the ototoxicity



Mechanism of aminoglycoside-induced outer hair cell death.

Rybak and Ramkumar, Kidney International (2007)

Renal arter

Nephrotoxicity

Renal vein

ureter

cortex Accumulates in epithelial cells of

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prox ma convu ate tu u ar ce s

oxidative stressDNA damage, lipid oxidation

apotosis and necrosis

tubuular dysfunction



mild rise in serum creatinine

proteinuria, casts

-- aminopeptidase.

Nephrotoxic potencies : Neomycin > tobramicin

In severe cases, produces renal tubular necrosis

= gentam c n > streptomyc n

antagonize factor V resulting in bleeding

Muscular Blockade: Neuromuscular junction

1. Pre-synaptic terminal2. Sarcolemma

.4. Acetylcholine receptor5. Mitochondria

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muscle



AG (curare-like)

Muscular blockade(tobra<genta<amika<kana< neomy)

Caution:Myasthenia gravispatients

calcium gluconate or neostigmine reverses this effect

VII. Therapeutic Use:

Streptomycinunusal mycobacterial infections in combinationwith other antimicrobial agents ( toxic )1000 mg/single or 500 mg double dose serumconcentration of 50-60 and 15-30 hg/ml

Pla ue

Tuberculosis

Bacterial endocarditis (strep + Penn G) replaced by(genta + PennG)

Tularemia (Strep or Genta)



Gentamicin: Ist choice; low cost, and reliable activity agnst all Gram (-) bacilli including infections

caused by pseudomonas aeruginosaIT or IV: used rarely as cuases local inflammation

-lactum-insensitive UTI’s

Bacterial endocarditisSepsisTopical as in burn patients

Tobramycin (Tobrex) (~ Gentamicin)

AmikacinBroadest spectrum, absobed rapidly after IM injection;Peak plasma concentration ~20ug/ml after 7.5 mg/kgn ec onNosocomial Gram (-) infections

Netilmicin~Gentamicincan be used for Gentamicin resistant bacteria

frequently used in topical ointments;administered oral to clean the bowel prior tobowel surgery (not absorbed, eliminated in thefeces, very toxic if administered I.M.)



Summary: Aminoglycosides

Most toxic; ototoxicit , rototoxicit , muscular blockade ,

Requires oxygen and changes in trasmembrane potentialto act on 30S ribosome

Use diminished as other Antibts became avl:

Limited spectrum Gram(-) Aerobesineffective in anerobeswill work in facultative bact in aerobe enviroment

conc in serum should be monitored

being reconsider due to resistance with Penn/CephMRSA?

Use for historical dis: Plague, TB

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Cephalosporins and Aminoglycosides